Biology subjects

Scott, J. A.

Publications and source records attributed to Scott, J. A..

4 recordsLinked to original sources

bioRxiv2025

Identification of non-coding elements associated with the evolutionary loss of digit 1.

Evolutionary loss of digits and limbs occurred many times during the diversification of tetrapods. The limbs of the earliest tetrapods were polydactylous, bearing as many 8 digits, but after the pentadactyly (five digits) was stabilized, no lineage evolved more than five digits per limb but many underwent digit loss. Within mammals, digit 1 (thumb on the forelimb or hallux on the hindlimb) is lost most frequently and is typically the first digit to disappear. Evidence from numerous studies of limb development shows that digit 1 development is controlled by mechanisms that are at least partially independent of the posterior 4 digits. In addition, evolutionary loss of digit 1 occurred independently in forelimbs and hindlimbs. Despite the frequency of digit loss in mammals, the underlying genetic mechanisms have not been uncovered. We used comparative genomics and bioinformatics to reconstruct the evolutionary history of genomic changes associated with digit 1 loss in the forelimbs and/or hindlimbs of 65 mammalian species. We identified a set of conserved non-coding elements that evolved in concert with independent (parallel) losses of digit 1. These elements, which are frequently near genes with known roles in digit development, underwent accelerated evolution in digit-reduced lineages. Furthermore, we find that elements with accelerated rates of evolution show significant loss of binding sites for transcription factors that are crucial for anterior digit development. The results suggest that cis-regulatory elements important for the development of digit 1 are evolutionarily accelerated in mammalian lineages that underwent reduction and loss of digit 1.

evolutionary biology↗

bioRxiv2019

Dynamic shifts of visual and saccadic signals in prefrontal cortical regions 8Ar and FEF

Active vision is a fundamental process by which primates gather information about the external world. Multiple brain regions have been studied in the context of simple active vision tasks in which a visual targets appearance is temporally separated from saccade execution. Most neurons have tight spatial registration between visual and saccadic signals, and in areas such as prefrontal cortex (PFC) some neurons show persistent delay activity that links visual and motor epochs and has been proposed as a basis for spatial working memory. Many PFC neurons also show rich dynamics, which have been attributed to alternative working memory codes and the representation of other task variables. Our study investigated the transition between processing a visual stimulus and generating an eye movement in populations of PFC neurons in macaque monkeys performing a memory guided saccade task. We found that neurons in two subregions of PFC, the frontal eye fields (FEF) and area 8Ar, differed in their dynamics and spatial response profiles. These dynamics could be attributed largely to shifts in the spatial profile of visual and motor responses in individual neurons. This led to visual and motor codes for particular spatial locations that were instantiated by different mixtures of neurons, which could be important in PFCs flexible role in multiple sensory, cognitive, and motor tasks.\n\nNew and NoteworthyA central question in neuroscience is how the brain transitions from sensory representations to motor outputs. The prefrontal cortex contains neurons that have long been implicated as important in this transition and in working memory. We found evidence for rich and diverse tuning in these neurons, that was often spatially misaligned between visual and saccadic responses. This feature may play an important role in flexible working memory capabilities.

neuroscience↗

bioRxiv2018

Coverage and timeliness of vaccination and the validity of routine estimates: Insights from a Vaccine Registry in Kenya

The benefits of childhood vaccines are critically dependent on vaccination coverage. We used a vaccine registry (as gold standard) in Kenya to quantify errors in routine coverage methods (surveys and administrative reports), to estimate the magnitude of survivor bias, contrast coverage with timeliness and use both measures to estimate population immunity.\n\nWe found coverage surveys in the 2nd year of life overestimate coverage by 2%. Compared to mean coverage in infants, static coverage at 12 months was exaggerated by 7-8% for third doses of oral polio, pentavalent (Penta3) and pneumococcal conjugate vaccines, and by 24% for the measles vaccine. Surveys and administrative coverage also underestimated the proportion of the fully immunised child by 10-14%. For BCG, Penta3 and measles, timeliness was 23-44% higher in children born in a health facility but 20-37% lower in those who first attended during vaccine stock outs.\n\nCoverage surveys in 12-23 month old children overestimate protection by ignoring timeliness, and survivor and recall biases.

epidemiology↗

bioRxiv2018

Loss of E-cadherin enhances IGF1-IGF1R pathway activation and sensitizes breast cancers to anti-IGF1R inhibitors

PurposeInsulin-like growth factor I (IGF1) signaling regulates breast cancer initiation and progression and associated cancer phenotypes. We previously identified E-cadherin (CDH1) as a repressor of IGF1 signaling and in this study examined how loss of E-cadherin affects IGF1R signaling and response to anti-IGF1R therapies in breast cancer.\n\nExperimental DesignBreast cancer cell lines were used to assess how altered E-cadherin levels regulate IGF1R signaling and response to two anti-IGF1R therapies. In situ proximity ligation assay (PLA) was used to define interaction between IGF1R and E-cadherin. TCGA RNA-seq and RPPA data was used to compare IGF1R activation in estrogen receptor positive (ER+) invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) tumors. ER+ ILC cell lines and xenograft tumor explant cultures were used to evaluate efficacy to IGF1R pathway inhibition in combination with endocrine therapy.\n\nResultsDiminished functional E-cadherin increased both activation of IGF1R signaling and efficacy to anti-IGF1R therapies. PLA demonstrated a direct endogenous interaction between IGF1R and E-cadherin at points of cell-cell contact. Increased expression of IGF1 ligand and levels of IGF1R phosphorylation were observed in E-cadherin deficient ER+ ILC compared to IDC tumors. IGF1R pathway inhibitors were effective in inhibiting growth in ER+ ILC cell lines and synergized with endocrine therapy and similarly IGF1R inhibition reduced proliferation in ILC tumor explant culture.\n\nConclusionsWe provide evidence that loss of E-cadherin hyperactivates the IGF1R pathway and increases sensitivity to IGF1R targeted therapy, thus identifying the IGF1R pathway as a potential novel target in E-cadherin deficient breast cancers.\n\nSTATEMENT OF SIGNIFICANCEIGF1R signaling is an attractive therapeutic target in breast cancer due to its regulation of proliferation, migration, and invasion. However, clinical trials targeting IGF1R have largely been unsuccessful due to lack of biomarkers to stratify patients for therapeutic response. In this study, we demonstrate loss of E-cadherin as a potential biomarker for response to anti-IGF1R therapy, and show efficacy of IGF1R inhibition in ER+ ILC in combination with endocrine therapy. Patients with ER+ ILC have poorer long-term outcomes than patients with ER+ IDC and have a propensity for increased late recurrences, highlighting the need for improved therapeutic strategies for this subtype of breast cancer. Here, we credential IGF1R inhibition as a novel therapeutic strategy in combination with endocrine therapy for the treatment of ER+ ILC.

cancer biology↗